Cycloheptylamine derivatives as anti-diabetic agents

ABSTRACT

Cycloalkylamine derivatives may be used for preventing or treating diseases in humans, animals, and have demonstrated efficacy specifically in treating type 2 diabetes. In an embodiment, the cycloalkylamine derivatives can include a compound selected from the group consisting of cycloheptanamine salts, cyclohexanamine salts, cyclopentanamine salts 1-cycloheptyl-[4,4′-bipyridin]-1-ium, N1,N2-dicycloheptyloxalamide, 1-[3′,5′-bis(trifluoromethyl)phenyl]-3-cycloheptylurea, 1,1′-(4-methyl-1,3-phenylene)bis(3-cycloheptylurea), 1-(2′-aminopyrimidin-4′-yl)-3-cycloheptylurea, 4-amino-N-(cycloheptylcarbamoyl)benzenesulfonamide, 4-(3′-cycloheptylureido)-N-(5″-methylisoxazol-3″-yl)benzenesulfonamide, N-(cycloheptylcarbamoyl)-4-methylbenzenesulfonamide, 1-cycloheptylguanidine hydrochloride, (E)-amino[(amino(cycloheptylamino)methylene)amino]methaniminium chloride, or a pharmaceutically acceptable salt thereof.

BACKGROUND 1. Field

The disclosure of the present patent application relates tocycloalkylamine derivatives that are demonstrated to treat certaindiseases in humans or animals. In particular, cycloheptylaminederivatives, and compositions including the compounds, are shown to beeffective in treating diabetes type-2.

2. Description of the Related Art

Increasing incidence of diabetes is considered to be one of the mostcommon concerns in the medical field today. In the U.S. alone, in 2015,over 30 million Americans aged 18 years or older were estimated to havediagnosed or undiagnosed diabetes—about 9.4% of the adult population. Ofthese, about 23 million were estimated to have been diagnosed withdiabetes, while over 7 million were undiagnosed. See “Statistics AboutDiabetes,” American Diabetes Association, athttps://www.diabetes.org/resources/statistics/statistics-about-diabetes.About 1.25 million American children and adults have type 1 diabetes;the rest have type 2 diabetes.

Diabetes is recognized as a chronic disease with high morbidity andmortality, posing an economic burden for developing countries [M. M.Engelgau, L. S. G., et al., Ann. Intern. Med., 140:945-950 (2004)]. Arecent study by WHO reveals that there were approximately 200 millionpeople globally, ranging age 20-80 years, suffering from diabetes. Thisfigure is expected to increase to 366 million by the year 2030. Diabeticpatients on prolonged exposure to uncontrolled hyperglycemia experienceseveral diabetic complications such as retinopathy, neuropathy,cataracts, nephropathy and cardiovascular complication.

Several drugs, such as sulfonylureas (glipizide and glyburide) andbiguanides (metformin) or a combination of metformin and sitagliptin,are presently available to reduce hyperglycemia in patients withdiabetes mellitus. However, these drugs typically can cause significantside effects.

Thus, anti-diabetic agents solving the aforementioned problems isdesired.

SUMMARY

Cycloalkylamine derivatives, as described herein, can provide effectiveanti-diabetic effects. These derivatives can include one or morecompounds selected from the group consisting of cycloheptanaminehydrochloride, cycloheptanamine hydrobromide,1-cycloheptyl-[4,4′-bipyridin]-1-ium chloride, andN1,N2-dicycloheptyloxalamide or a pharmaceutically acceptable saltthereof.

Several cycloalkylamine derivatives were demonstrated to provideeffective hypoglycemic activity after administration of 1.0 μM/kg inStreptozotocin- (STZ-) induced diabetic rats. Blood glucose levels weremeasured and compared with a standard control drug.

The anti-diabetic activities of these novel derivatives showed betterresults than most commercially available anti-diabetic type-2 drugs. Thein-vitro and in-vivo testing results showed that these novel compoundsprovide better efficacy in patients with type 2 diabetes. The methodsused to synthesize these derivatives afforded better yields, in shortertime, yielding high purities.

These and other features of the present findings will become readilyapparent upon further review of the following specification.

These and other features of the present invention will become readilyapparent upon further review of the following specification anddrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a bar graph showing in vivo anti-hyperglycemic effect onfasting blood glucose levels over time, ranging from 0 minute to 480minutes, and at 1440 minutes, in STZ-induced diabetic rats, comparing adose of 1.0 μM/kg compound 2a with control. Results are means SEM; n=6rats; * P<0.05, ** P<0.01, vs. STZ control.

FIG. 1B is a bar graph showing in vivo anti-hyperglycemic effect onfasting blood glucose levels over time, ranging from 0 minute to 480minutes, and at 1440 minutes, in STZ-induced diabetic rats, comparing adose of 1.0 μM/kg compound 2b with control. Results are means±SEM; n=6rats; * P<0.05, ** P<0.01, vs. STZ control.

FIG. 1C is a bar graph showing in vivo anti-hyperglycemic effect onfasting blood glucose levels over time, ranging from 0 minute to 480minutes, and at 1440 minutes, in STZ-induced diabetic rats, comparing anoral dose of 1.0 μM/kg compound 2c with control. Results are means SEM;n=6 rats; * P<0.05, ** P<0.01, vs. STZ control.

FIG. 1D is a bar graph showing in vivo anti-hyperglycemic effect onfasting blood glucose levels over time, ranging from 0 minutes to 480minutes, and at 1440 minutes, in STZ-induced diabetic rats, comparing adose of 1.0 μM/kg compound 2d with control. Results are means±SEM; n=6rats; * P<0.05, ** P<0.01, vs. STZ control.

FIG. 2A is a bar graph showing the in vitro effects on insulin secretionof compound 2a at concentrations of 10⁻¹⁵, 10⁻¹², and 10⁻⁹ M, comparedto control, in both the absence and presence of 2.8 mM glucose. Resultsare means of triplicates±SEM; * P<0.05, ** P<0.01, *** P<0.001, fromrelative basal control.

FIG. 2B is a bar graph showing the in vitro effects on insulin secretionof compound 2b at concentrations of 10⁻¹⁵, 10⁻¹², and 10⁻⁹ M, comparedto control, in both the absence and presence of 2.8 mM glucose. Resultsare means of triplicates±SEM; * P<0.05, ** P<0.01, *** P<0.001, fromrelative basal control.

FIG. 2C is a bar graph showing the in vitro effects on insulin secretionof compound 2c at concentrations of 10⁻¹⁵, 10⁻¹², and 10-9 M, comparedto control, in both the absence and presence of 2.8 mM glucose. Resultsare means of triplicates±SEM; * P<0.05, ** P<0.01, *** P<0.001, fromrelative basal control.

FIG. 2D is a bar graph showing the in vitro effects on insulin secretionof compound 2d at concentrations of 10¹⁵, 10¹², and 10⁻⁹ M, compared tocontrol, in both the absence and presence of 2.8 mM glucose. Results aremeans of triplicates±SEM; * P<0.05, ** P<0.01, *** P<0.001, fromrelative basal control.

FIG. 3A is a bar graph showing the in vitro effect on insulin secretionof compound 6 at concentrations of 10⁻¹⁵, 10⁻¹², and 10⁻⁹ M, compared tocontrol, in both the absence and presence of 2.8 mM glucose. Results aremeans of triplicates±SEM; * P<0.05, ** P<0.01, from relative basalcontrol, and #P<0.05, ##P<0.01 from glucose 2.8 mM.

FIG. 3B is a bar graph showing the in vitro effect on insulin secretionof compound 9c at concentrations of 10⁻¹⁵, 10⁻¹², and 10⁻⁹ M, comparedto control, in both the absence and presence of 2.8 mM glucose. Resultsare means of triplicates±SEM; * P<0.05, ** P<0.01, from relative basalcontrol, and #P<0.05, ##P<0.01 from glucose 2.8 mM.

FIG. 3C is a bar graph showing the in vitro effect on insulin secretionof compound 9d at concentrations of 10⁻¹⁵, 10⁻¹², and 10⁻⁹ M, comparedto control, in both the absence and presence of 2.8 mM glucose. Resultsare means of triplicates±SEM; * P<0.05, ** P<0.01, from relative basalcontrol, and #P<0.05, ##P<0.01 from glucose 2.8 mM.

FIG. 3D is a bar graph showing the in vitro effect on insulin secretionof compound 9f at concentrations of 10⁻¹⁵, 10⁻¹², and 10⁻⁹ M, comparedto control, in both the absence and presence of 2.8 mM glucose. Resultsare means of triplicates±SEM; * P<0.05, ** P<0.01, from relative basalcontrol, and #P<0.05, ##P<0.01 from glucose 2.8 mM.

FIG. 3E is a bar graph showing the in vitro effect on insulin secretionof compound 10 at concentrations of 10⁻¹⁵, 10⁻¹², and 10⁻⁹ M, comparedto control, in both the absence and presence of 2.8 mM glucose. Resultsare means of triplicates±SEM; * P<0.05, ** P<0.01, from relative basalcontrol, and #P<0.05, ##P<0.01 from glucose 2.8 mM.

FIG. 3F is a bar graph showing the in vitro effect on insulin secretionof compound 11 at concentrations of 10⁻¹⁵, 10⁻¹², and 10⁻⁹ M, comparedto control, in both the absence and presence of 2.8 mM glucose. Resultsare means of triplicates±SEM; * P<0.05, ** P<0.01, from relative basalcontrol, and #P<0.05, ##P<0.01 from glucose 2.8 mM.

FIG. 4 depicts the synthesis scheme for cycloalkylamine derivatives2a-d.

FIG. 5 depicts the synthesis scheme for compound 6.

FIG. 6 depicts the synthesis scheme for compound 8.

FIG. 7 depicts the general synthesis scheme for cycloheptyl ureaderivatives 9a-f.

FIG. 8 is a table depicting the various R and R substituents incycloheptyl urea derivatives 9a-f.

FIG. 9 depicts the synthesis scheme for compound 10.

FIG. 10 depicts the synthesis scheme for compound 11.

Similar reference characters denote corresponding features consistentlythroughout the attached drawings.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Cycloalkylamine derivatives described herein may be used for preventingor treating diseases in humans, animals and have demonstrated efficacyspecifically in treating type 2 diabetes. According to one embodiment,the derivatives can provide effective hypoglycemic activity.

In an embodiment, the cycloalkylamine derivatives can include a compoundselected from the group consisting of cyclohexanamine hydrochloride,cyclopentanamine hydrochloride, cycloheptanamine hydrochloride,cycloheptanamine hydrobromide, 1-cycloheptyl-[4,4′-bipyridin]-1-iumchloride, N1,N2-dicycloheptyloxalamide,1-[3,5-bis(trifluoromethyl)phenyl]-3-cycloheptylurea,1,1′-(4-methyl-1,3-phenylene)bis(3-cycloheptylurea),1-(2-aminopyrimidin-4-yl)-3-cycloheptylurea,4-amino-N-(cycloheptylcarbamoyl)benzenesulfonamide,4-(3-cycloheptylureido)-N-(5-methylisoxazol-3-yl)benzenesulfonamide,N-(cycloheptylcarbamoyl)-4-methylbenzenesulfonamide,1-cycloheptylguanidine hydrochloride,(E)-amino[(amino(cycloheptylamino)methylene)amino]methaniminiumchloride, or a pharmaceutically acceptable salt thereof.

In an embodiment, the cycloalkylamine derivatives can include a compoundhaving the following structural formula:

whereinR is selected from the group consisting of

R₁ is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

The cycloheptylamine derivatives synthesized in high yields, with highpurity. The cycloheptylamine derivatives can be used in providinganti-diabetic effects. These derivatives may be prepared in any suitablepharmaceutical formulation, with any suitable pharmaceutical excipients,for administration to a patient in any suitable manner as generallyknown in the industry and that may be determined or designated by amedical practitioner treating the patient.

According to one embodiment, the cycloheptylamine derivatives provideeffective treatment of fasting blood glucose.

Certain embodiments provide a method for the preparation and/or use ofcompounds 2a-d, as set forth in Example 4.

Certain embodiments provide a method for the preparation and/or use ofcompound 6, as shown in FIG. 5 and described in Example 5.

Certain embodiments provide a method for the preparation and/or use ofcompound 8, as shown in FIG. 6 and as set forth in Example 7.

According to certain embodiments, the cycloheptylamine derivativesinclude cycloheptyl urea derivatives 9a-f, as shown in FIGS. 7 and 8,and as set forth in Example 8.

According to an embodiment, the cycloheptylamine derivatives includecycloheptyl guanidine derivative compound 10 and 11, as prepared inExample 9.

According to an embodiment, the cycloheptylamine derivatives includecompounds 2a-d, as prepared in Example 4.

As described herein, in-vitro and in-vivo testing revealed that compound2a demonstrated particular potency in providing anti-diabetic activity.Compound 2a produced significant reduction in blood glucose levelswithin 1 hour, and lasting as long as at least 8 hours. Compound 2a alsosignificantly stimulated insulin secretions, both in the absence andpresence of glucose.

The present findings are illustrated by the following Examples.

EXAMPLES

Pharmacology

The in-vitro and in-vivo testing results showed that cycloheptylaminederivatives provide better efficacy in rats with type 2 diabetes thanmany marketed anti-diabetic type-2 drugs. Several cycloheptylaminederivatives were demonstrated to provide effective hypoglycemic activityafter administration of 1.0 μM/kg in Streptozotocin- (STZ-) induceddiabetic rats. Blood glucose levels were measured and compared with astandard control drug. The test results showed that compound 2a producesboth reductions in blood glucose levels and stimulation of insulinproduction.

Example 1

Evaluation of Some Novel Cycloalkylamine Hydrochloride Salts 2a-d onFasting Blood Glucose (FBG)

The following cycloalkylamine hydrochloride salts 2a-d were synthesizedand evaluated:

Rats injected with (Streptozotocin STZ) showed significant increases inplasma glucose level and kidney weight along with decreases in seruminsulin and body weight in comparison with non-diabetic rats. Thesesymptoms indicated the development of diabetes characterized by chronicand persistently elevated plasma glucose levels.

STZ induces diabetes by selectively destroying the insulin producingpancreatic endocrine cells. Decreased body weight in STZ-induceddiabetic rats is believed to be caused by dehydration, breakdown andcatabolism of fats and proteins. Increased catabolic reactions uponadministration of STZ results in muscle wasting and subsequently bodyweight loss.

Compound 2a was orally administrated to the treated groups of diabeticrats at a dose of 1.0 μM/kg. Glucose levels in their blood were followedover 8.0 hours. Diabetic rats treated with compound 2a showedsignificant reduction in blood glucose levels after one hour and up to 8hours after treatment compared to control diabetic rats (FIGS. 1A-1D).Compounds 2b-d were orally administrated to the treated groups ofdiabetic rats at a dose of 1.0 μM/kg. Blood glucose levels weremonitored at 0, 30 minutes, 60 minutes, 2 hours, 4 hours, 6 hours, 8hours, and then again at 24 hours. See FIGS. 1A to 1D.

Example 2 The Effects of Compounds 2a on Insulin Secretion by βTC6 Cells

The secretion of insulin by βTC6 cells was measured using the high rangeinsulin Sandwich ELISA kit. The 2.8 mM glucose gave a mild insulinresponse around 3000 pmol/l and was used in testing the effect ofcompounds 2a-d.

FIG. 2A show the in-vitro effects of the most potent compound 2a at10⁻¹⁵, 10⁻¹², and 10⁻⁹ M concentrations on insulin secretion in absenceand presence of 2.8 mM glucose.

In the absence of glucose, concentrations of 10⁻¹⁵ and 10⁻¹² M ofcompound 2a significantly stimulated insulin secretions compared to thebasal control. In the presence of 2.8 mM glucose, concentrations (10⁻¹⁵,10⁻¹², and 10⁻⁹ M) of compound 2a stimulated insulin secretionssignificantly compared to basal insulin secretion. Taken together thein-vivo and in-vitro results indicate that compound 2a is a potentanti-diabetic compound.

FIGS. 2B to 2D show the in-vitro effects of compounds 2b-d,respectively, at 10⁻¹⁵, 10⁻¹², and 10⁻⁹ M concentrations on insulinsecretion in the absence and presence of 2.8 mM glucose.

In the absence of glucose, compounds 2b-d did not significantlystimulate insulin secretions compared to the basal control. In presenceof 2.8 mM glucose, compounds 2b-d stimulated insulin secretionssignificantly compared to basal insulin secretion. Compound 2c at 10⁻⁹ Malso significantly potentiated the glucose-stimulated insulin secretion.

Example 3 Evaluation of Cyloheptylamine Derivatives 6, 9, 9d 9f 10, and11 on Fasting Blood Glucose

The same testing procedure was used as in Example 2 above, to evaluatethe effect of cycloheptylamine derivatives 6, 9c, 9d, 9f, 10, and 11,provided below:

FIGS. 3A-3F show the in-vitro effects on insulin secretion demonstratedby cycloheptylamine derivatives at 10⁻¹⁵, 10⁻¹², and 10⁻⁹ Mconcentrations, in both the absence and presence of 2.8 mM glucose.

Compound 6 significantly stimulated insulin secretions compared to thebasal control. In the presence of 2.8 mM glucose, compound 6significantly stimulated insulin secretions compared to basal insulinsecretion as well as insulin secretion in the presence of glucose (FIG.3A). Compounds 9c, 9d, 9f, 10, and 11 each demonstrated significantstimulation of insulin secretion in the presence of 2.8 mM glucose,though not to a statistically significant degree in the absence ofglucose (FIGS. 3B to 3F).

Example 4 Synthesis of Cycloalkylamine Hydrochloride Salts

The following method was used to synthesize the desired derivatives,provide better yields, in shorter time, yielding high purities. Anexemplary reaction scheme for synthesizing cycloalkylamine salts(compounds 2a-2d) is provided in FIG. 4, where R represents cycloalkylgroups.

General Procedure for the Synthesis of Cycloalkylamine HydrochlorideSalts

Cycloalkyl amine derivative was dissolved in a minimal amount ofmethanol and treated with excess hydrochloric acid or hydrobromic acidto form chloride or bromide salt. The salt was collected from diethylether using vacuum filtration to provide compounds 2a-d.

Production of compounds 2a and 2b involved use of cycloalkylaminederivatives in excess of HCl or HBr, respectively. Compound 2c wasprepared using cyclopentylamine and excess HCl where, compound 2d wasprepared using cyclohexylamine and excess HCl.

Analysis Results Cycloheptanamine Hydrochloride (2a)

Off white solid, yield: 94%, mp 217-218° C.; ¹H-NMR (DMSO-d₆) (δ, ppm):1.36-1.60 (m, 10H, cycloheptyl ring), 1.82 (m, 2H, cycloheptyl ring),3.98 (m, 1H, cycloheptyl ring), 8.24 (brs, 3H, NH₃, cycloheptylamine,D₂O-exchange); ¹³C-NMR (DMSO-d₆) (δ, ppm): 23.2, 27.2, 32.3, 52.7; Anal.Calcd for C₇H₁₆ClN: C, 56.18; H, 10.78; N, 9.36; Found: C, 56.63; H,10.85; N, 9.64.

Cycloheptanamine Hydrobromide (2b)

Off white solid, yield: 93%, mp 213-214° C.; ¹H-NMR (DMSO-d₆) (δ, ppm):1.36-1.61 (m, 10H, cycloheptyl ring), 1.86-1.88 (m, 2H, cycloheptylring), 3.90 (m, 1H, cycloheptyl ring), 6.60 (brs, 3H, NH₃(cycloheptylamine, D₂O-exchange); ¹³C-NMR (DMSO-d₆) (δ, ppm): 22.8,26.8, 31.9, 52.3; Anal. Calcd for C₇H₁₆BrN: C, 43.31; H, 8.31; N, 7.22;Found: C, 43.76; H, 8.38; N, 7.50.

Cyclopentanamine, Hydrochloride (2c)

Off white solid, yield: 91%, mp 209-211° C.; ¹H-NMR (CDCl₃, 400 MHz) (δ,ppm): 1.64-1.65 (m, 2H, cyclopentyl ring), 1.85-2.05 (m, 5H, cyclopentylring), 2.31 (m, 1H, cyclopentyl ring), 3.65 (m, 1H, cyclopentyl ring),8.27 (brs, 3H, NH₃, cyclopentylamine, D₂O-exchange); ¹³C-NMR (CDCl₃, 100MHz) (δ, ppm): 23.5, 30.5, 52.1 (cyclopentyl ring); Anal. Calcd forC₅H₁₂ClN: C, 49.38; H, 9.95; N, 11.52; Found: C, 49.83; H, 10.02; N,11.80.

Cyclohexanamine, Hydrochloride (2d)

Light brown solid, yield: 92%, mp 215° C.; ¹H-NMR (DMSO-d_(b)) (δ, ppm):1.33 (m, 4H, cyclohexyl ring), 1.59 (m, 4H, cyclohexyl ring), 2.90 (m,2H, cyclohexyl ring), 3.58 (m, 1H, cyclohexyl ring), 7.38 (s, 3H, NH₃(cyclohexylamine, D₂O-exchange); ¹³C-NMR (DMSO-d₆) (δ, ppm): 24.8, 25.6,33.1, 48.5 (cyclohexyl ring); Anal. Calcd for C₆H₁₄ClN: C, 53.13; H,10.40; N, 10.33; Found: C, 53.58; H, 10.47; N, 10.61.

Synthesis of Cycloheptylamine Derivatives Example 5

Cycloheptylamine derivatives were prepared according to the reactionscheme depicted in FIG. 5.

Synthesis of Compound 6

4,4′-bipyridine (10 mmol, 1.56 g) and 1-chloro-2,4-dinitrobenzene (10mmol, 2.02 g) were dissolved in 5 ml acetone and the vessel was closedimmediately and subjected to microwave irradiation at 58° C. for about20 min. The precipitate was collected by filtration, washed with diethylether, and dried under vacuum to afford the final product,1-(2,4-dinitrophenyl)-[4,4′-bipyridin]-1-ium (5), as a light greenpowders (3.26 g, yield: 91%); ¹H-NMR [CDCl₃, 400 MHz]: (δ, ppm) 7.87 (d,2H, aromatic, J=4.0 Hz), 8.13 (d, 1H, aromatic, J=8.0 Hz), 8.53 (d, 2H,aromatic, J=4.0 Hz), 8.67 (d, 2H, J=8.0 Hz), 8.79 (d, 1H, aromatic,J=8.0 Hz), 9.10 (d, 2H, aromatic, J=8.0 Hz), 9.23 (s, H, aromatic);¹³C-NMR [CDCl₃, 100 MHz]: (δ, ppm) 156.89, 150.00, 149.54, 145.69,142.84, 141.97, 138.32, 131.07, 130.51, 126.03, 122.63, 122.60.

Compound 5 (2 mmol, 0.65 g) from (Example 5) was dissolved in 3 mLethanol/water (1:1 by volume ratio), and corresponding cycloheptylamine(2.4 mmol, 0.31 ml) was added. The mixture was subjected to microwaveirradiation at 130° C. for 30 min. The precipitate formed and afterfiltering, compound 6 (1-cycloheptyl-[4,4′-bipyridin]-1-ium chloride(6)) was isolated as dark-gray in yield 89%, mp 102° C., IR (KBr, cm⁻¹):3023 (C—H aromatic), 2927 (C—H aliphatic), 1638 (C═N); ¹H-NMR (D₂O, 400MHz,]: (δ, ppm) 1.44-2.08 (m, 12H, cycloheptyl ring), 4.69 (m, 1H,cycloheptyl ring), 7.66 (d, 2H, J=6.3 Hz), 8.14 (d, 2H, J=6.7 Hz), 8.52(d, 2H, J=6.3 Hz), 8.78 (d, 2H, J=6.7 Hz); ¹³C-NMR (D₂O, 400 MHz,]: (δ,ppm) 23.9, 26.4, 35.4, 73.8 (cycloheptyl ring), 122.3, 125.8, 142.5,143.0, 149.8, 153.3 (bipyridine ring); Anal. Calcd for C₁₇H₂₁ClN₂: C,70.70; H, 7.33; N, 9.70; Found: C, 71.15; H, 7.40; N, 9.46.

Example 7 Synthesis of Compound 8

Compound 8 was prepared according to the reaction scheme depicted inFIG. 6. N1,N2-dicycloheptyloxalamide (8). Oxalyl chloride (0.46 mmol,0.04 ml) in dry dichloromethane (5 ml) was added dropwise to a solutionof cycloheptylamine (0.61 mmol, 0.08 ml) in dry dichloromethane (10 ml)containing triethylamine (0.61 mmol, 0.62 ml) (See FIG. 6). The reactionmixture was stirred at room temperature for 1.5 h. The solvent was thenevaporated and the residue was quenched with water. The resultingprecipitate was filtered, dried and recrystallized from methanol toyield compound 8 (92%) as a pale yellow solid, mp 232° C., IR (KBr,cm⁻¹): 3299 (NH), 3042 (C—H aromatic), 2930 (C—H aliphatic), 1651 (C═O);¹H-NMR [CDCl₃, 400 MHz]: (δ, ppm) 1.47-1.93 (m, 24H, cycloheptyl ring),3.88-3.90 (m, 2H, cycloheptyl ring), 7.44 (br, 2H, —NH,D₂O-exchangeable); ¹³C NMR [CDCl₃, 100 MHz]: (δ, ppm) 23.9, 27.9, 34.6,50.9 (cycloheptyl ring), 158.7 (C═O); Anal. Calcd for C₁₆H₂₈N₂O₂: C,68.53; H, 10.06; N, 9.99; Found: C, 68.98; H, 10.13; N, 10.27.

Example 8 Synthesis of Cycloheptyl-Urea Derivatives

Compounds 9a-f were prepared according to the reaction scheme depictedin FIG. 6 (with R and R₁ defined in the table depicted in FIG. 7). To asolution of the respective amine (10 mmol, 2.31 g) in acetonitrile (15ml), the respective isocyanate derivative was added (FIGS. 7 and 8). Thereaction mixture was stirred at room temperature for 2-3 hrs. Theprogress of the reaction was monitored by TLC and after completion; theprecipitate formed was filtered, washed with ethanol, and dried to givethe product, compounds 9a-f, shown below:

1-[3,5′-Bis(trifluoromethyl)phenyl]-3-cycloheptylurea (9a). White solid,yield: 91%, mp 169-170° C.; IR (KBr, cm⁻¹): 3340 (N—H urea), 3122 (C—Haromatic), 2930 (C—H aliphatic), 1659 (C═O, urea); ¹H-NMR [DMSO-d₆, 400MHz]: (δ, ppm) 1.41-1.54 (m, 10H, cycloheptyl ring), 1.78-1.79 (m, 2H,cycloheptyl ring), 3.80-3.82 (m, 1H, cycloheptyl ring), 6.41 (d, 1H,—NH, D₂O-exchangeable, J=8.0 Hz), 7.50 (s, 11H, aromatic), 8.03 (s, 21,aromatic), 9.01 (s, 1H, —NH, D₂O-exchangeable); ¹³C-NMR [DMSO-d₆, 100MHz]: (δ, ppm) 23.9, 28.1, 35.1, 50.7 (cycloheptyl ring), 113.7, 117.5(aromatic), 119.7-127.9 (CF₃), 130.5-131.5 (aromatic), 143.0 (aromatic),154.8 (C═O, urea); Anal. Calcd for C₁₆H₁₈F₆N₂O: C, 52.18; H, 4.93; N,7.61; Found: C, 52.63; H, 5.00; N, 7.89.

1,1′-(4″-Methyl-1″,3″-phenylene) bis(3-cycloheptylurea) (9b). Whitesolid, yield: 78%, mp 281-282° C.; IR (KBr, cm⁻¹): 3319 (N—H urea), 2927(C—H aliphatic), 1638 (C═O, urea); ¹H-NMR [DMSO-d₆, 400 MHz]: (δ, ppm)1.56-1.73 (m, 20H, cycloheptyl ring), 2.06 (m, 4H, cycloheptyl ring),2.16 (s, 3H, CH₃), 4.17 (m, 2H, cycloheptyl ring), 5.42 (d, 2H, —NH,D₂O-exchange, J=8.0 Hz), 7.21 (s, 1H, aromatic), 7.48-7.50 (m, 2H,aromatic), 8.05 (brs, 2H, —NH, D₂O-exchange); ¹³C-NMR [DMSO-d₆, 100MHz]: (δ, ppm) 11.8 (CH₃), 23.9, 28.1, 35.3, 50.2 (cycloheptyl ring),114.7, 117.8, 127.1, 129.1, 131.2, 136.2 (aromatic), 154.7 (C═O, urea);Anal. Calcd for C₂₃H₃₆N₄O₂: C, 68.97; H, 9.06; N, 13.99; Found: C,69.42; H, 9.13; N, 14.27.

1-(2′-Aminopyrimidin-4′-yl)-3-cycloheptylurea (9c). White solid, yield:80%, mp 139-141° C.; IR (KBr, cm⁻¹): 3477, 3405 (NH₂), 3307 (N—H urea),2927 (C—H aliphatic), 1699 (C═O, urea), 1535 (C═C aromatic); ¹H-NMR[DMSO-d₆, 400 MHz]: (δ, ppm) 1.25-1.55 (m, 10H, cycloheptyl ring),1.70-1.75 (m, 2H, cycloheptyl ring), 3.89-3.94 (m, 1H, cycloheptylring), 5.56 (d, 1H, NH, cycloheptylamine, D₂O-exchange, J=8.0 Hz), 5.63(d, 1H, H₅-pyrimidine ring, J=6.0 Hz), 6.19 (brs, 2H, NH₂,D₂O-exchange), 7.01 (brs, 1H, NH, D₂O-exchange), 7.58 (d, 1H,H₆-pyrimidine ring, J=6.0 Hz); ¹³C-NMR [DMSO-d₆, 100 MHz]: (δ, ppm)23.9, 28.2, 35.5, 50.1 (cycloheptyl ring), 95.4 (C5-pyrimidine), 154.7(C6-pyrimidine), 156.3 (C4-pyrimidine), 163.8 (C═O, urea), 164.5(C2-pyrimidine); Anal. Calcd for C₁₂H₁₉N₅O: C, 57.81; H, 7.68; N, 28.09;Found: C, 58.25; H, 7.75; N, 28.37.

4-Amino-N-(cycloheptylcarbamoyl)benzenesulfonamide (9d). White solid,yield: 91%, mp 235-236° C.; IR (KBr, cm⁻¹): 3384,3349 (NH₂), 3190 (N—Hurea), 2924 (C—H aliphatic), 1683 (C═O, urea), 1597 (C═C aromatic),1310, 1150 (—SO₂NH₂); ¹H-NMR [DMSO-d₆, 400 MHz]: (δ, ppm) 1.34-1.61 (m,10H, cycloheptyl ring), 1.88 (m, 2H, cycloheptyl ring), 3.63-3.68 (m,1H, cycloheptyl ring), 5.79 (s, 2H, NH₂, D₂O-exchangeable, J=8.0 Hz),6.54 (d, 2H, aromatic, J=6.0 Hz), 7.27 (brs, 1H, —NH, D₂O-exchangeable),8.22 (d, 2H, aromatic, J=8.0 Hz), 10.45 (s, 1H, —NH, D₂O-exchangeable);¹³C-NMR [DMSO-d₆, 100 MHz]: (δ, ppm) 23.5, 27.7, 32.8, 51.9 (cycloheptylring), 112.8, 127.2, 133.1, 152.4 (aromatic), 161.6 (C═O, urea); Anal.Calcd for C₁₄H₂₁N₃O₃S: C, 54.00; H, 6.80; N, 13.49; S, 10.30; Found: C,54.45; H, 6.87; N, 13.77; S, 10.57.

4-(3′-Cycloheptylureido)-N-(5″-methylisoxazol-3″-yl)benzenesulfonamide(9e). White solid, yield 82%, mp 245° C.; IR (KBr, cm⁻¹): 3360 (NH),3108 (C—H aromatic), 2932 (C—H aliphatic), 1688 (C═O), 1590 (C═Caromatic); ¹H-NMR [DMSO-d₆, 400 MHz]: (δ, ppm) 1.40-1.53 (m, 10H,cycloheptyl ring), 1.77 (m, 2H, cycloheptyl ring), 2.26 (s, 3H, CH₃),3.64 (m, 1H, cycloheptyl ring), 6.09 (s, 1H, aromatic), 6.27 (d, 1H,—NH, D₂O-exchange, J=8.0 Hz), 7.50 (d, 2H, aromatic, J=8.0 Hz), 7.65 (d,2H, aromatic, J=8.0 Hz), 8.77 (s, 1H, —NH, D₂O-exchange), 11.19 (s, 1H,—NH, D₂O-exchange); ¹³C-NMR [DMSO-d₆, 100 MHz]: (δ, ppm) 12.5 (CH₃),21.4, 25.4, 30.5, 56.5 (cycloheptyl ring), 95.7 (methylisoxazole C),112.9, 129.3, 135.2, 142.9 (aromatic), 153.7 (methylisoxazole C), 158.4(C═O), 170.3 (methylisoxazole C); Anal. Calcd for C₁₈H₂₄N₄O₄S: C, 55.08;H, 6.16; N, 14.28; S, 8.17; Found: C, 55.51; H, 6.22; N, 14.55; S, 8.15.

N-(Cycloheptylcarbamoyl)-4-methylbenzenesulfonamide (9f). White solid,yield: 94%, mp 241° C.; IR (KBr, cm⁻¹): 3142 (N—H urea), 2932 (C—Haliphatic), 1655 (C═O, urea); ¹H-NMR [DMSO-d₆, 400 MHz]: (δ, ppm)1.34-1.61 (m, 10H, cycloheptyl ring), 1.86-1.88 (m, 2H, cycloheptylring), 2.28 (s, 3H, CH₃), 3.63-3.68 (m, 1H, cycloheptyl ring), 7.12 (d,2H, phenyl ring, J=8.0 Hz), 7.55 (d, 2H, phenyl ring, J=8.0 Hz) 7.65(brs, 2H, NH, D₂O-exchange); ¹³C-NMR [DMSO-d₆, 100 MHz]: (δ, ppm) 23.5(CH₃), 27.5, 32.8, 52.1, 58.9 (cycloheptyl ring), 127.2, 128.4, 136.2,137.7 (phenyl ring), 163.3 (C═O, urea); Anal. Calcd for C₁₅H₂₂N₂O₃S: C,58.04; H, 7.14; N, 9.02; S, 10.33. Found: C, 58.49; H, 7.21; N, 9.30; S,10.61.

Example 9 Synthesis of Cycloheptyl Guanidine Derivatives

Referring to FIGS. 9 and 10, a mixture of cycloheptylamine (1 mmol, 0.11g), cyanamide (1 mmol, 0.04 g), 4 M HCl-AcOEt (0.1 ml) and EtOH (2 ml)was subjected to microwave irradiation at 100° C. for 45 min. Theprecipitated solid was filtered and washed with AcOEt and H₂O to givecompound 10, having the following structural formula:

1-Cycloheptylguanidine hydrochloride (10): Off-white solid, yield 64%,mp 106° C.; IR (KBr, cm⁻¹): 3429, 3388 (NH₂), 3147 (N—H), 2930 (C—Haliphatic), 1560 (C═C aromatic); ¹H-NMR [DMSO-d₆, 400 MHz]: (δ, ppm)1.38-1.68 (m, 10H, cycloheptyl ring), 1.80-1.81 (m, 2H, cycloheptylring), 3.93-3.95 (m, 1H, cycloheptyl ring), 4.13-4.15 (brs, 1H, —NH,D₂O-exchange), 6.68 (brs, 2H, —NH.HCl, D₂O-exchange), 8.03 (brs, 2H,NH₂, D₂O-exchange); ¹³C-NMR [DMSO-d₆, 100 MHz]: (δ, ppm) 21.4, 25.4,30.5, 50.2 (cycloheptyl ring), 160.2 (C═NH); Anal. Calcd for C₈H₁₈ClN₃:C, 50.12; H, 9.46; N, 21.92; Found: C, 50.52; H, 9.53; N, 22.20.

Cycloheptylamine (2.1 mmol, 254.5 mg) was added to a solution ofdicyandiamide (2.1 mmol, 176.6 mg) in 3.7 ml of dry CH₃CN, and TMSCl(trimethylsilyl chloride) (2.3 mmol, 228.1 mg) was slowly added dropwiseto the mixture. The mixture was stirred and irradiated for 15 minutes at150° C., using microwave reactor. After the mixture was cooled down toapproximately 50° C., isopropyl alcohol (6.3 mmol, 0.49 ml) was addedslowly, and the mixture was further stirred and irradiated at 125° C.for 1 minute. The precipitation of the biguanide hydrochloride salt waswashed with CH₃CN twice to afford compound 11, having the structuralformula shown below:

(E)-Amino[(amino(cycloheptylamino)methylene)amino]methaniminium chloride(11). The analytical sample of compound 11 was obtained byrecrystallization from iPrOH as a white powder; yield 61%, mp 283° C.;IR (KBr, cm⁻¹): 3439, 3335 (NH₂), 3192 (N—H), 2925 (C—H aliphatic), 1560(C═C aromatic); ¹H-NMR [DMSO-d₆, 400 MHz]: (δ, ppm) δ 1.40-1.59 (m, 10H,cycloheptyl ring), 1.78 (m, 2H, cycloheptyl ring), 3.64 (m, 1-H,cycloheptyl ring), 5.19 (brs, 1H, —NH, D₂O-exchange), 6.84 (brs, 2H,—NH.HCl, D₂O-exchange), 8.23 (brs, 4H, NH₂, D₂O-exchange); ¹³C-NMR[DMSO-d₆, 100 MHz]: (δ, ppm) 23.5, 27.7, 32.5, 52.0 (cycloheptyl ring),160.8 (C═N), 163.3 (C═N); Anal. Calcd for C₉H₂₀ClN₅: C, 46.25; H, 8.62;N, 29.96; Found: C, 46.70; H, 8.69; N, 30.24.

It is to be understood that the cycloalkylamine derivatives and methodsdisclosed here are not limited to the specific embodiments describedabove, but encompass any and all embodiments within the scope of thegeneric language of the following claims enabled by the embodimentsdescribed herein, or otherwise shown in the drawings or described abovein terms sufficient to enable one of ordinary skill in the art to makeand use the claimed subject matter.

We claim:
 1. Cycloalkylamine derivatives, comprising compounds selectedfrom the group consisting of cycloheptylamine hydrochloride,cycloheptylamine hydrobromide, cyclopentylamine hydrochloride,cyclohexylamine hydrochloride, or a pharmaceutically acceptable saltthereof.